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Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2016) | Viewed by 82078

Special Issue Editor

1. Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401, USA
2. Department of Otolaryngology, Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, Charleston, SC 29425, USA
Interests: head and neck squamous cell carcinoma; HNSCC; immune regulation; immunotherapy; premalignant oral lesions

Special Issue Information

Dear Colleagues,

While decades have passed since the declaration of the war on cancer, progress in the battle has not been uniform for all cancer types. For certain, many advances have been made and there exists a spectrum of surgical, chemotherapeutic and radiological treatment approaches. In recent years, immunotherapeutic approaches have become increasingly more prominent, with melanoma being most prominently targeted in immunological treatment trials. Challenges in optimal use of immunotherapy include tumor-induced immune subversion, its compatibility with other conventional treatments, extent of tumor immunogenicity, immune-prevention strategies, and understanding the limitations of immunotherapy. This issue aims to discuss these challenges in particular as they relate to cancers that have been understudied as candidates for immunotherapy. It is with a wider scope of understanding of the immunological challenges posed by the heterogeneity of cancers that customized immunotherapy can be included in the armament for cancers that have not been in the forefront of immunological treatment investigations.

Prof. Dr. M. Rita I. Young
Guest Editor

Manuscript Submission Information

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Keywords

  • immunotherapy
  • cancer vaccines
  • immune subversion
  • cancer
  • immunosuppression
  • cytokines
  • immune regulation
  • cancer prevention

Published Papers (13 papers)

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Editorial

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364 KiB  
Editorial
Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy
by M. Rita I. Young
Int. J. Mol. Sci. 2017, 18(1), 127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18010127 - 11 Jan 2017
Viewed by 4422
Abstract
A number of immune therapeutic approaches have been transitioning from being experimental to being incorporated as standard approaches, either alone or in conjunction with other therapies.[...] Full article
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Research

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3107 KiB  
Article
In Vitro Assessment of the Expression and T Cell Immunogenicity of the Tumor-Associated Antigens BORIS, MUC1, hTERT, MAGE-A3 and Sp17 in Uterine Cancer
by Anke Vanderstraeten, Sandra Tuyaerts, Tina Everaert, Rieta Van Bree, Godelieve Verbist, Cathérine Luyten and Frederic Amant
Int. J. Mol. Sci. 2016, 17(9), 1525; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091525 - 09 Sep 2016
Cited by 3 | Viewed by 4889
Abstract
Background: While immunotherapy moved to the forefront of treatment of various cancers, it remains underexplored for uterine cancer. This might be due to the small patient population with advanced endometrial carcinoma and uterine sarcoma. Data about immunotherapeutic targets are scarce in endometrial carcinoma [...] Read more.
Background: While immunotherapy moved to the forefront of treatment of various cancers, it remains underexplored for uterine cancer. This might be due to the small patient population with advanced endometrial carcinoma and uterine sarcoma. Data about immunotherapeutic targets are scarce in endometrial carcinoma and lacking in uterine sarcoma. Methods: Expression of five tumor-associated antigens (TAA) (BORIS, MUC1, hTERT, MAGE-A3 and Sp17) was validated in uterine tumor samples by immunohistochemistry (IHC) and/or quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). TAA immunogenicity was analyzed by determining spontaneous T cell responses towards overlapping peptide pools covering the whole TAA in patient blood. Results: At mRNA level, MAGE-A3 and Sp17 were overexpressed in a minority of patients and BORIS was moderately overexpressed (26% in endometrial carcinoma and 62% in uterine sarcoma). hTERT was overexpressed in the vast majority of tumors. On protein level, MUC1 was upregulated in primary, recurrent and metastatic EMCAR and in metastatic US tumors. hTERT protein was highly expressed in both normal and malignant tissue. Spontaneous TAA-specific T cell responses were detected in a minority of patients, except for hTERT to which T cell responses occurred more frequently. Conclusions: These data point to MUC1 and hTERT as most suitable targets based on expression levels and T cell immunogenicity for use in immunotherapeutic regimens. Full article
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Communication
Restoration of Immune Responsiveness to Glioma by Vaccination of Mice with Established Brain Gliomas with a Semi-Allogeneic Vaccine
by Sebastiano Gattoni-Celli and M. Rita I. Young
Int. J. Mol. Sci. 2016, 17(9), 1465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091465 - 02 Sep 2016
Cited by 5 | Viewed by 4120
Abstract
Prior studies had shown the clinical efficacy of a semi-allogeneic glioma vaccine in mice with lethal GL261 gliomas. This was confirmed in the present study. As subcutaneous vaccination resulted in protection against tumor in the brain, the present study assessed the impact of [...] Read more.
Prior studies had shown the clinical efficacy of a semi-allogeneic glioma vaccine in mice with lethal GL261 gliomas. This was confirmed in the present study. As subcutaneous vaccination resulted in protection against tumor in the brain, the present study assessed the impact of this vaccination of mice bearing established GL261 brain gliomas on their cytokine production upon in vitro exposure to tumor-derived products. Mice with established GL261 brain gliomas were vaccinated subcutaneously with H-2b GL261 glioma cells fused with H-2d RAG-neo cells or with a mock vaccine of phosphate-buffered saline. The results of these analyses show that the presence of GL261 tumor-conditioned medium resulted in increased production of Th1, inflammatory and inhibitory cytokines by spleen cells from control mice and from vaccinated glioma-bearing mice. In contrast, spleen cells of tumor-bearing, mock-vaccinated mice produced lower levels of cytokines in the presence of tumor-conditioned media. However, these results also show that there was not a heightened level of cytokine production in the presence of tumor-conditioned medium by spleen cells of vaccinated mice over the production by spleen cells of control mice. Overall, these results show that vaccination slows growth of the GL261 tumors to the point where GL261-vaccinated mice do not show the signs of morbidly or splenic dysfunction exhibited by unvaccinated, late stage glioma-bearing mice. Full article
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Article
Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer
by Rim Hojeij, Sonia Domingos-Pereira, Marianne Nkosi, Dalila Gharbi, Laurent Derré, John T. Schiller, Patrice Jichlinski and Denise Nardelli-Haefliger
Int. J. Mol. Sci. 2016, 17(7), 1125; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071125 - 14 Jul 2016
Cited by 17 | Viewed by 5544
Abstract
Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral [...] Read more.
Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC. Full article
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Article
Increased Efficacy of Brentuximab Vedotin (SGN-35) in Combination with Cytokine-Induced Killer Cells in Lymphoma
by Laura Esser, Hans Weiher and Ingo Schmidt-Wolf
Int. J. Mol. Sci. 2016, 17(7), 1056; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071056 - 01 Jul 2016
Cited by 9 | Viewed by 5730
Abstract
Brentuximab vedotin (SGN-35) is an antibody–drug conjugate with a high selectivity against CD30+ cell lines and more than 300-fold less activity against antigen-negative cells. In the last years, the results of many in vitro and in vivo studies have led to the [...] Read more.
Brentuximab vedotin (SGN-35) is an antibody–drug conjugate with a high selectivity against CD30+ cell lines and more than 300-fold less activity against antigen-negative cells. In the last years, the results of many in vitro and in vivo studies have led to the fast approval of this drug to treat lymphoma patients. Another innovative method to treat tumor cells including lymphoma cells is the use cytokine-induced killer (CIK) cells, which have also been approved and proven to be a safe treatment with only minor adverse events. In this study, a possible additive effect when combining SGN-35 with CIK cells was investigated. The combinational treatment showed that it reduces the viability of CD30+ cell lines significantly in vitro. Additionally, the amount of lymphoma cells was significantly reduced when exposed to CIK cells as well as when exposed to SGN-35. A significant negative effect of SGN-35 on the function of CIK cells could be excluded. These results lead to the assumption that SGN-35 and CIK cells in combination might achieve better results in an in vitro setting compared to the single use of SGN-35 and CIK cells. Further investigations in in vivo models must be conducted to obtain a better understanding of the exact mechanisms of both treatments when applied in combination. Full article
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Article
Hypoxia Inducible Factor 1 (HIF-1) Recruits Macrophage to Activate Pancreatic Stellate Cells in Pancreatic Ductal Adenocarcinoma
by Na Li, Yang Li, Zengxun Li, Chongbiao Huang, Yanhui Yang, Mingxiao Lang, Junli Cao, Wenna Jiang, Yu Xu, Jie Dong and He Ren
Int. J. Mol. Sci. 2016, 17(6), 799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060799 - 03 Jun 2016
Cited by 74 | Viewed by 8092
Abstract
Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1α and HIF-1β, in which HIF-1β is constitutively expressed. HIF-1 upregulates several hypoxia-responsive proteins, including angiogenesis factors, glycolysis solution enzymes, and cell survival proteins. HIF-1 is also associated with [...] Read more.
Hypoxia inducible factor 1 (HIF-1) is a transcription factor composed of two subunits, namely, HIF-1α and HIF-1β, in which HIF-1β is constitutively expressed. HIF-1 upregulates several hypoxia-responsive proteins, including angiogenesis factors, glycolysis solution enzymes, and cell survival proteins. HIF-1 is also associated with the degree of inflammation in the tumor region, but the exact mechanism remains unclear. This study aims to identify the molecular mechanism of recruiting monocytes/macrophages by HIF-1α in pancreatic ductal adenocarcinoma (PDAC) and the effects of macrophages on pancreatic stellate cells (PSCs). Immunohistochemistry (IHC) was performed for cluster of differentiation 68 (CD68), HIF-1α, and chemical chemokines 2 (CCL2). Western blot, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation assay, and The Cancer Genome Atlas (TCGA) were used to verify the correlation between HIF-1α and CCL2 at protein and nucleic acid levels. Monocytes/macrophages were co-cultured with PSCs to observe their interaction. Samples showed significant correlation between CD68 and HIF-1α (t-test, p < 0.05). HIF-1α recruited monocytes/macrophages by promoting CCL2 secretion. Moreover, macrophages could accelerate the activation of PSCs. HIF-1α might promote inflammation and fibrosis of PDAC through CCL2 secretion, which may provide a novel target to treat PDAC patients. Full article
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Article
Nrf2 Expressions Correlate with WHO Grades in Gliomas and Meningiomas
by Wen-Chiuan Tsai, Dueng-Yuan Hueng, Chii-Ruey Lin, Thomas C. K. Yang and Hong-Wei Gao
Int. J. Mol. Sci. 2016, 17(5), 722; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050722 - 13 May 2016
Cited by 21 | Viewed by 5248
Abstract
Background: Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as Nrf2) is associated with cellular progression and chemotherapeutic resistance in some human cancers. We tested the relationship between Nrf2 expression and survival of patients with primary brain tumors (PBTs). Methods: In [...] Read more.
Background: Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as Nrf2) is associated with cellular progression and chemotherapeutic resistance in some human cancers. We tested the relationship between Nrf2 expression and survival of patients with primary brain tumors (PBTs). Methods: In order to realize Nrf2 protein expression in gliomas, Western blot analysis was performed in normal brain tissue and U87MG, LN229, GBM8401 and U118MG glioma cell lines protein lysates. Then, U87MG, LN229, and GBM8401 mRNA were applied to performed quantitative RT-PCR for detect Nrf2 gene expression in glioma cell lines. At last, immunohistochemical analysis was used to determine the expression of Nrf2 in samples from 178 PBTs and 10 non-neoplastic brain tissues. Results: In these included in vitro studies, both Nrf2 protein and mRNA expression in all human glioma cell lines were higher than normal brain tissue. Similarly, on the viewpoint of immunohistochemistry, Nrf2 expression in gliomas were positively correlated with World Health Organization (WHO) grades. Additionally, compared with the expression of Nrf2 in non-neoplastic brain tissue, expression in meningiomas was of a stronger intensity and was present in a higher percentage of cells. Furthermore, scores were significantly higher in WHO grade II than in WHO grade I meningiomas. Finally, overall survival tended to be shorter in patients whose PBTs had higher expression of Nrf2, although the correlation was not statistically significant. Conclusions: Nrf2 overexpression positively correlated with WHO grade in gliomas and meningiomas. On the other hand, Nrf2 immunohistochemical stain could help pathologists to differentiate atypical meningiomas from benign tumors. Therefore, Nrf2 expression may be a useful biomarker to predict WHO grade and cellular behavior of PBTs. Full article
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Article
Development and Characterization of a Humanized Anti-HER2 Antibody HuA21 with Potent Anti-Tumor Properties in Breast Cancer Cells
by Ruilin Li, Siyi Hu, Yan Chang, Zhihui Zhang, Zhao Zha, Hui Huang, Guodong Shen, Jing Liu, Lihua Song and Wei Wei
Int. J. Mol. Sci. 2016, 17(4), 563; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040563 - 15 Apr 2016
Cited by 9 | Viewed by 6336
Abstract
Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor [...] Read more.
Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy. Full article
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205 KiB  
Communication
The Utilization of the Immune System in Lung Cancer Treatment: Beyond Chemotherapy
by Carmen W. H. Chan, Stephen K. W. Tsui, Bernard M. H. Law, Winnie K. W. So, Fiona W. K. Tang and Cho-Lee Wong
Int. J. Mol. Sci. 2016, 17(3), 286; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030286 - 25 Feb 2016
Cited by 7 | Viewed by 5232
Abstract
Lung cancer is ranked first worldwide as one of the main cancers in terms of prevalence and mortality rate. The development of effective treatment strategies against lung cancer is therefore of paramount importance. Traditionally, chemotherapy was employed in the treatment of various cancers. [...] Read more.
Lung cancer is ranked first worldwide as one of the main cancers in terms of prevalence and mortality rate. The development of effective treatment strategies against lung cancer is therefore of paramount importance. Traditionally, chemotherapy was employed in the treatment of various cancers. However, the non-specific nature of the actions of chemotherapeutic drugs and the potential for tumors to develop resistance to these drugs may render chemotherapy a less favorable option for cancer treatment. Immunotherapy provides an alternative strategy for this purpose. It involves the utilization of the immune system and the immune effector cells to elicit an immune response to the tumors, thereby eliminating them. Strategies include the administration of pro-inflammatory cytokines for immune stimulation, the removal of immunological checkpoints using monoclonal antibodies, and the use of cancer vaccines to enhance immunity against tumors. This article summarizes the above strategies, highlights the reasons why immunotherapy is superior to chemotherapy for the purpose of tumor removal, and reviews the recent clinical studies comparing the clinical outcomes of patients undergoing immunotherapy and chemotherapy. The article also describes advances in immunotherapeutic strategies for the treatment of lung cancer. Full article
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Review

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Review
Development of Novel Immunotherapies for Multiple Myeloma
by Ensaf M. Al-Hujaily, Robyn A. A. Oldham, Parameswaran Hari and Jeffrey A. Medin
Int. J. Mol. Sci. 2016, 17(9), 1506; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091506 - 08 Sep 2016
Cited by 21 | Viewed by 8344
Abstract
Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for [...] Read more.
Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. Full article
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563 KiB  
Review
Targeting the Tumor Microenvironment: The Protumor Effects of IL-17 Related to Cancer Type
by Joseph Fabre, Jerome Giustiniani, Christian Garbar, Frank Antonicelli, Yacine Merrouche, Armand Bensussan, Martine Bagot and Reem Al-Dacak
Int. J. Mol. Sci. 2016, 17(9), 1433; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091433 - 30 Aug 2016
Cited by 101 | Viewed by 8906
Abstract
The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory [...] Read more.
The inflammatory process contributes to immune tolerance as well as to tumor progression and metastasis. By releasing extracellular signals, cancerous cells constantly shape their surrounding microenvironment through their interactions with infiltrating immune cells, stromal cells and components of extracellular matrix. Recently, the pro-inflammatory interleukin 17 (IL-17)-producing T helper lymphocytes, the Th17 cells, and the IL-17/IL-17 receptor (IL-17R) axis gained special attention. The IL-17 family comprises at least six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. Secreted as disulfide-linked homo- or heterodimers, the IL-17 bind to the IL-17R, a type I cell surface receptor, of which there are five variants, IL-17RA to IL-17RE. This review focuses on the current advances identifying the promoting role of IL-17 in carcinogenesis, tumor metastasis and resistance to chemotherapy of diverse solid cancers. While underscoring the IL-17/IL-17R axis as promising immunotherapeutic target in the context of cancer managing, this knowledge calls upon further in vitro and in vivo studies that would allow the development and implementation of novel strategies to combat tumors. Full article
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Review
Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?
by Gloria Mittica, Sofia Genta, Massimo Aglietta and Giorgio Valabrega
Int. J. Mol. Sci. 2016, 17(7), 1169; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071169 - 20 Jul 2016
Cited by 52 | Viewed by 7818
Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents [...] Read more.
Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. Full article
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Review
The Immunogenicity of Colorectal Cancer in Relation to Tumor Development and Treatment
by Natasja L. De Vries, Marloes Swets, Alexander L. Vahrmeijer, Marianne Hokland and Peter J. K. Kuppen
Int. J. Mol. Sci. 2016, 17(7), 1030; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071030 - 29 Jun 2016
Cited by 34 | Viewed by 6541
Abstract
Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important [...] Read more.
Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor. Full article
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